Daunorubicin / Cytarabin (1) – Vyxeos®

• Clinical trials
  • The benefit assessment is based on the pivotal registration trial CLTR0310-301. This was a randomised, open-label, multicentre, phase III trial with a parallel-group design (1:1) and two treatment arms, in which daunorubicin / cytarabine (liposomal formulation) was compared with cytarabine and daunorubicin (7+3 regimen).

Adult patients with newly diagnosed treatment-related acute myeloid leukaemia (t-AML) or AML with myelodysplastic changes (AML-MRC)

• For daunorubicin / cytarabine (liposomal formulation) for the treatment of adults with newly diagnosed treatment-related acute myeloid leukaemia (t-AML) or AML with myelodysplastic changes (AML-MRC), there is considerable additional benefit.
• In the overall assessment, a considerable additional benefit is identified for daunorubicin / cytarabine (liposomal formulation) compared with cytarabine and daunorubicin (7+3 regimen) and docetaxel in the treatment of adults with newly diagnosed treatment-induced acute myeloid leukaemia (t-AML) or AML with myelodysplastic changes (AML-MRC).
• Mortality – Overall survival
  • Treatment with daunorubicin / cytarabine (liposomal formulation) was associated with a statistically significant prolongation of overall survival compared with treatment with cytarabine and daunorubicin (7+3 regimen) (hazard ratio: 0.69 [0.52; 0.90], p-value = 0.005).
  • The median survival time in the treatment group receiving daunorubicin / cytarabine (liposomal formulation) was 9.56 months, compared with 5.95 months in the treatment group receiving cytarabine and daunorubicin (7+3 regimen), meaning that treatment with daunorubicin / cytarabine (liposomal formulation) resulted in a median survival benefit of 3.6 months.
  • This result demonstrates an extension in overall survival, which is regarded as a significant improvement.
• Morbidity – Event-Free Survival
  • Event-free survival (EFS) was defined in the study as the time from randomisation until the occurrence of one of the following events: • failure of induction therapy (persistent disease), • relapse following confirmed CR or CRi, • death from any cause.
  • However, based on the available results for the EFS endpoint, it is not possible to draw sufficiently robust conclusions regarding the therapeutic effects in terms of failure of the curative treatment approach – and thus the attempt at a cure – for the following reasons:
  • Of the patients who did not achieve CR or CRi and were therefore included in the analysis as induction failures, a significant proportion received a stem cell transplant following the event ‘failure of induction therapy’ (intervention arm: n=12 (15.0 %); control arm: n=14 (14.1%).
  • Furthermore, not all patients who achieved CR or CRi subsequently received consolidation chemotherapy or a stem cell transplant. However, subsequent consolidation therapy is a prerequisite for assuming that the therapeutic approach is curative overall.
  • The vast majority of patients received anti-leukaemia therapies, including stem cell transplants with, in principle, curative potential, during the follow-up phase of the study: 116 patients in the intervention arm (75.8 per cent) and 107 patients in the control arm (68.6 per cent).
  • Based on the available information, it can be assumed that patients were censored for the endpoint ‘event-free survival’ at the time of salvage therapy or anti-leukaemic treatment not in accordance with the protocol. Censoring is therefore not independent of the endpoint under consideration, as it cannot be ruled out that patients with a poorer prognosis and a higher risk of relapse or death received salvage therapy. This approach constitutes informative censoring and carries the risk of biasing the results.
  • For these reasons, the results for the EFS endpoint are presented only as supplementary information in this assessment. It is not possible to draw a sufficiently reliable conclusion regarding the extent of the additional benefit.
• quality of life
  • No data on health-related quality of life were collected in the study.
• Side effects
  • In the study, the observation period for adverse events (AEs) differs significantly between the intervention and control arms. Therefore, the event duration analyses submitted by the pharmaceutical manufacturer in its statement regarding the endpoints of serious adverse events (SAEs), severe adverse events (AEs with a CTCAE grade ≥ 3), as well as AEs of particular interest to the present assessment.
  • With regard to SAEs, there is a statistically significant increase with treatment using daunorubicin/cytarabine (liposomal formulation) compared with cytarabine and daunorubicin (7+3 regimen).
  • In its statement, the pharmaceutical manufacturer indicates that the higher rate of SAE and the shorter time to onset of a SAE are attributable to the fact that patients in the intervention arm were frequently treated on an outpatient basis during the consolidation phase, whereas in the control arm treatment was almost exclusively inpatient.
  • The G-BA concludes that, on the one hand, the difference in treatment setting between the intervention and control arms (outpatient vs. inpatient) is verifiable on the basis of the information in the study report and additional details provided in the pharmaceutical manufacturer’s statement. On the other hand, any necessary hospitalisation of a patient is documented as a SAE; therefore, taking into account the existing clinical and treatment situation, it can be assumed that differences in the SAE data may have been caused by the different treatment settings (outpatient vs. inpatient) and that there is therefore a relevant bias in the data on SAEs.
  • When considering the results on side effects as a whole, there is a hint of a disadvantage based on the data on SAEs; however, it is assumed that there is a relevant bias tending to be to the detriment of the intervention arm. Taking into account the relevant statements by medical experts on the clinical significance of the adverse effects occurring with daunorubicin/cytarabine (liposomal formulation), and against the background of the aim of curative therapy, this assessment does not assume that the side effects represent such a significant disadvantage as to need to be weighed against the results for other patient-relevant endpoints.
• Overall assessment
  • In its overall assessment, the G-BA concludes that daunorubicin / cytarabine (liposomal formulation) offers a considerable extent of additional benefit compared with cytarabine and daunorubicin (7+3 regimen).

Courtesy translation only, please refer to the German original.